Sympathetic vasoconstrictor responsiveness is blunted in contracting human skeletal muscle. In contrast, alpha-adrenergic vasoconstrictor responsiveness is not affected by hypoxia in resting human subjects. In animal models exercise and hypoxia can act alone or in combination to blunt sympathetic vasoconstriction. In human skeletal muscle, it is unknown if combined exercise and hypoxia act synergistically to attenuate alpha receptor-mediated vasoconstriction. The proposed experiments will determine whether 1) sympatholysis will be augmented during combined exercise and hypoxia (low PO2 and low O2 content); 2) the more metabolically sensitive alpha-2 adrenergic receptors will be associated with any augmented sympatholysis during hypoxic exercise; 3) sympatholysis will be augmented under conditions of decreased arterial O2 content alone; and 4) hypoxia (low PO2 and low O2 content) or low arterial O2 content alone alters sympatholysis in exercising leg muscle (i.e. large muscle mass). The strength of the proposed experimental design is that we will study the basic mechanisms of circulatory control during exercise in humans. The results of these experiments will provide important new information about the interactions between neural and local factors controlling blood flow to exercising human skeletal muscle.